Over 350 million people worldwide are chronic carriers of hepatitis B virus (HBV) - over one million in the United States alone. Chronic hepatitis B infection is a major risk for the development of primary hepatocellular carcinoma (HCC). More than 500,000 people in the world die each year of HCC and most cases are associated with HBV. Interferon-a and lamivudine are the only FDA approved drugs for treatment of chronic HBV infection. There are frequent side effects and complications associated with the use of interferon-a, which also has limited efficacy with only 30% of patients responding favorably to treatment. Lamivudine is a safe drug but frequent occurrences of drug resistant mutants are observed with extended therapy. In most cases, drug withdrawal is associated with complete recrudescence of viral replication. Therefore, there is an urgent need for novel or alternative treatment methods for HBV therapy. Ganoderma lucidum spores used in Traditional Chinese Medicine (TCM) have been shown to have antiviral and anticancer activity against HBV and HCC in human patients in China. In this proposal we plan to use the woodchuck model of hepatitis B virus infection to investigate experimentally the potential of Ganoderma lucidum for prevention and treatment of HCC. The long-term goal of the project is to determine the antiviral activity Ganoderma lucidum spores against HBV and the anticancer activity of Ganoderma lucidum spores for prevention and treatment of human HCC. The specific aims are to: 1) determine the antiviral activity of Ganoderma lucidum spores against the woodchuck hepatitis virus (WHV) as a preclinical test of their potential for treatment of HBV infection and 2) determine the activity of the Ganoderma lucidum spores in the prevention and treatment of HCC in woodchucks with experimentally induced, chronic WHV infection.